A nice pair

I often despair when I read some of the papers that pass for phage therapy science, so it’s nice to see a couple of very solid contributions published this month. Neither are attention-grabbing reports of cures of patients who had failed antibiotic therapy and were at death’s door. You won’t see a word about them in the popular press. But both papers–one basic science, one applied–do a lot more than all the sensationalized case studies put together to make phage therapy a reality.

The basic science paper addresses what is seen as one of the weaknesses of phage therapy: the ability of bacteria to spontaneously develop resistance to phage. Phage and bacteria have been battling it out for billions of years and its no surprise that both have developed portfolios of measures and countermeasures. CRISPR is just one of these.

Enterococci used to be considered a normal intestinal commensal, but acquired virulence genes along with antibiotic resistance genes in the modern hospital environment. A large fraction of Enterococcus infections are no longer treatable with antibiotics, and the CDC now classifies them as a serious threat to public health.

Phage therapy of VRE (vancomycin-resistant Enterococci) seems a plausible alternative, but phage resistance emerges in as little as 48 hours in mouse models. That would seem to rule out phage therapy, or at least spark a search for phage formulations less prone to being rendered ineffective.

But maybe resistance to phage comes at a cost. We know this for antibiotic resistance: resistant strains are (in general) less fit than susceptible strains, and less able to cause virulent infections.

It turns out that the same thing is true for phage resistance, and we now know the reason why. The dominant mode of resistance to phage in this study is an alteration in the carbohydrates in the Enterococcus cell wall. Phage use these to recognize their target hosts and the changes make the bacteria invisible to the phage.

But evolution drives phage to pick recognition targets that are important to the host and thus not readily changed. It turns out that the altered cell walls render the bacteria more susceptible to certain antibiotics, and less able to bind to the lining of the intestine. Adhesion to epithelial cells is critical for virulence: bacteria can’t attack host cells if they can’t stick to them.

Phage therapy, at least in this model, thus seems to have three potentially beneficial modes of action: it can kill the bacteria directly; it can make them less virulent; it can make them more susceptible to adjuvant antibiotic therapy. A win all the way around (if you are not an Enterococcus).

It remains to be seen how general a phenomenon this is, but it would not be surprising to find that it is common. Someone just needs to do the work.

Turning phage from lab pets to products

I’ve long believed that phage therapy has been held back by its low barrier to entry. Phage are so easy and cheap and quick to find and grow and play with that they enable dilettantism. Academics tend to be terribly naive about all the steps required to translate an observation in the controlled confines of the lab into a product that can be reliably manufactured at scale by people with high school educations and used by health care professionals who know nothing and care less about the beauty and coolness of the technology.

That means solving a hundred (at least) little and big problems, every one of which, left unsolved, means you have no product. This is why phage therapy has seemed poised for a breakout for decades, and keeps not breaking out.

So I’m pleased to report that AmpliPhi Bio has published this paper describing the formulation, manufacture, characterization and verification of an anti-S. aureus phage cocktail. AmpliPhi looked like roadkill a couple of years ago, losing both their CEO and 90% of their market cap in a particularly bad week.

But they’ve regrouped, slogged on, and reported some promising results in patients who had failed antibiotic therapy for systemic S. aureus infections.

I’m also glad to see that they are moving on from systemic infections–antibiotic failure is much too rare to comprise a viable market for phage therapy.

Instead they are focusing on lung infections (ie. Staph pneumonia). This is a much bigger market, and an indication for which standard anti-MRSA drugs (vancomycin and daptomycin) work poorly. In addition, phage are cleared much more slowly from the lungs than they are from the bloodstream, making effective dosing much more practical.

Not that there are no challenges. They found that a pretty high dose of phage was required to get a serious reduction in bacterial loads:

4 x 10⁸ phage as a minimal dose is not a lot, but mice aren’t very big. The standard factor for scaling mouse doses to humans is 250. That works out to 10¹¹ phage per dose in humans. That’s a lot, but no dealbreaker–about the yield expected from a liter of culture after purification and processing. Just one more of the hundred problems that needs to be solved. I hope they do it.